In an attempt to better understand the neuroendocrine mechanisms involved in the control of gonadotropin and prolactin secretion in health and disease, we plan to further investigate the inhibitory role of dopamine (DA) and endogenous opiate peptides on gonadotronin release in healthy women and in hypogonadotropic states. Recently, we have presented data suggesting an increased hypothalamic DA and opioid peptides inhibition of gonadotropins during the late follicular and mid-luteal but not the early follicular phase of the menstrual cycle. To determine whether estrogen and/or progesterone modulate the inhibitory effect of endogenous opiates on LRF neuronal activity, we plan to do sequential naloxone infusion in agonadal women with or without exogenous estrogen and/or progesterone administration. To test our hypothesis that a reduction in the excessive DA and/or opioid inhibition of LRF-LH system may be involved in the initiation of the midcycle gonadotropin surge, DA, beta-endorphin or their receptor blockers will be administered mid-cycle to normal cycling women. Previously, we have demonstrated an LH increment following the administration of both DA and opiate receptor antagonists in both patients with hypothalamic hypogonadotropic amenorrhea and those with prolactinoma; however, patients with prepubertal gonadotropin levels failed to respond. To determine whether previous LH non-responders are a distinct neuroendocrine disorder or whether they represent a more severe form of hypogonadotropinism, we plan to repeat naloxone studies after exogenous LRF priming. We then plan to determine the role of endogenous DA and/or opiate peptides in the inhibition of the LRF-LH system in 4 additional hypogonadotropic states: postpartum, post-complete prolactinomectomy, anorexia nervosa and puberty. Finally, we plan to assess whether a DA excess attenuates the pulsatile LH release in prolactinoma patients by monitoring changes in the circulating gonadotropin levels during the infusion of a DA receptor antagonist, metoclopramide.